Arnold 2004.

Study characteristics
Methods	7‐centre USA trial consisting of a 6‐week, open‐label, dose‐titration phase (Part A) and a 2‐week, double‐blind, randomised, parallel‐group, placebo‐controlled withdrawal trial (Part B) with 2 arms d‐MPH placebo
Participants	Number of patients screened: 116 Part A Number of participants included: 89 (72 boys, 17 girls) Number of participants followed up: 76 Number of withdrawals: 13 DSM‐IV diagnosis of ADHD (combined 80%) Age range: 6‐16 years IQ: not stated MPH‐naive: 71.9% Ethnicity: not stated Country: USA Comorbidity: not stated Comedication: not stated Additional sociodemographics: none Part B Number of participants included: 75 (61 boys, 14 girls) Number followed up in each arm: MPH 34, placebo 39 Number of withdrawals in each arm: MPH 1, placebo 1 DSM‐IV diagnosis of ADHD (combined (80%), hyperactive‐impulsive (0%), inattentive (20%)) Age range: 6‐16 years IQ: > 70 (mean not stated) MPH‐naive (MPH 82.9%, placebo 62.5%) Ethnicity: white (MPH 80%, placebo 75%), African American (MPH 14.3%, placebo 12.5%), Hispanic (MPH 5.7%, placebo 12.5%) Country: USA Setting: outpatient clinic and hospital Comorbidity: not stated Comedication: antihistamines, non‐steroidal anti‐inflammatory agents, multi‐vitamins, nasal decongestants or other analgesics or antipyretics (MPH 34.3%, placebo 40.0%) Additional sociodemographics: none No significant differences in baseline demographics were noted between the 2 groups. Thus, slightly more treatment‐naive participants were receiving d‐MPH than placebo Inclusion criteria 6‐17 years of age Enrolled in school DSM‐IV diagnosis of ADHD, any subtype Within 30% of normal body weight Able to participate for the full 8 weeks Exclusion criteria History or evidence of cardiovascular, renal, respiratory (other than asthma/allergy), endocrine or immune system disease History of substance abuse Hypersensitivity to d,l‐MPH or other stimulants Treatment with any investigational drug within 30 days of screening Other significant CNS disorders Treatment with antidepressants, neuroleptics/antipsychotics, mood stabilisers, anticonvulsants, beta‐blockers, alpha‐2‐agonists, other stimulants, thyroid medications, long‐term oral steroids or sedatives/hypnotics Concurrent treatment with other psychoactive drug
Interventions	Part B Participants were randomly assigned to d‐MPH at optimised dose or placebo Number randomised to each group: MPH 35, placebo 40 Mean MPH dosage: 68.6% of d‐MPH continuers and 79.5% of placebo participants were receiving 20 mg at end of Part B, mean (SD) not stated Administration schedule: 10 mg twice daily. Time points 7 am to 8 am and 11:30 am to 12 pm Duration of intervention: 2 weeks Titration period: 6 weeks, initiated before randomisation Treatment compliance: not stated
Outcomes	ADHD symptoms (Part B) SNAP, teacher‐rated at baseline and at end of treatment SNAP, parent‐rated at baseline and at end of treatment, 3 and 6 h post‐dose Non‐serious AEs (Parts A and B) Monitoring of AEs and changes from baseline in vital signs (pulse and BP), physical examination and clinical laboratory parameters throughout the trial
Notes	Comments from trial authors Limitations Study design: treatment effects in such trials may be larger than those seen in unselected populations because, in the randomised withdrawal phase, responders were pre‐selected from the open‐label titration phase to the drug phase. Another possible limitation is the duration of discontinuation (2 weeks) Key conclusion of trial authors d‐MPH is safe, tolerable and effective, with a 6‐hour duration of effect suggested by significant differences from placebo at 6 hours on double‐blind discontinuation Inclusion of MPH responders only/exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes Any withdrawals due to AEs: no Funding source: trial was supported by the Celgene Corporation Email correspondence with trial authors: October 2013. Supplemental information regarding additional information was received. However, trial authors advised us to contact the sponsoring drug company for additional information. This process has been difficult, and no further communication was attempted to request additional information. (see Storebø 2015a)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was central, irrespective of whether the drug was pre‐packaged and pre‐randomised, or if it was bottled and labelled by an unblinded dispenser who had no contact with participants and kept the other staff blind
Allocation concealment (selection bias)	Low risk	Randomisation was central. "In all industry studies I have been involved with, either the drug was pre‐packaged and pre‐randomized or it was bottled and labeled by an unblinded dispenser who had no contact with patients and kept the other staff blind"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind. In Part B, participants/guardians and medical personnel were blinded to the drug. Also, d‐MPH was available in tablets, each identical in appearance to a matching placebo. trial drug (or placebo) was dispensed in bottles containing a weekly supply, labelled for use at “Home” and “School”, with the strength designated “A,” “B” or “C”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind. In Part B, participants/guardians and medical personnel were blinded to the drug
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT sample was used in analysis of efficacy parameters: participants who received d‐MPH and had a Part B baseline efficacy evaluation and ≥ 1 post‐baseline assessment Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	Unclear risk	No protocol published